IMMUNOHISTOCHEMICAL DETECTION OF 4-HYDROXY-2-NONENAL ADDUCTS IN ALZHEIMERS-DISEASE IS ASSOCIATED WITH INHERITANCE OF APOE4

Cumulative oxidative damage, including lipid peroxidation, Is a centra l component of cellular aging and is thought to play a role in the pat hogenesis of late-onset Alzheimer's disease CAD), Lipid peroxidation p roduces several cytotoxic aldehydes, one of the most potent being 4-hy droxy-2-nonenal (HNE), We have shown previously that HNE is a potent n eurotoxin that covalently modifies and cross-links neuronal cytoskelet al protein in neuroglial cultures, suggesting that HNE may contribute to the pathogenesis of AD. In addition to aging, inheritance of the ep silon 4 allele of APOE is the other major risk factor for development of late-onset AD; however, the mechanisms through which aging and apol ipoprotein E isoforms may collaborate in the onset or progression of A D are not known. We tested the hypothesis that HNE may yield a particu lar type of protein modification, pyrrole adduction, and that this may contribute to the pathogenesis of AD, Our data demonstrated that HNE formed pyrrole adducts with protein, Polyclonal antiserum was raised t hat specifically recognized HNE pyrrole adducts, and immunohistochemic al analysis was performed on hippocampus and temporal cortex of 10 Pat ients with histologically verified AD, Pyramidal neuron cytoplasm was immunoreactive in 4 of 4 APOE4 homozygotes, 2 of 3 APOE3/4 heterozygot es, and none of 3 APOE3 homozygotes (P < 0.05), The pattern of stainin g was highly suggestive of neurofibrillary tangles as the primary immu noreactive structure. These data suggest that differences in neuronal protein modification by HNE may account in part for the APOE-associate d stratification of risk for late-onset AD.